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Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness

BACKGROUND: Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, suc...

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Autores principales: Meshnik, Lana, Bar-Yaacov, Dan, Kasztan, Dana, Neiger, Tali, Cohen, Tal, Kishner, Mor, Valenci, Itay, Dadon, Sara, Klein, Christopher J., Vance, Jeffery M., Nevo, Yoram, Züchner, Stephan, Ovadia, Ofer, Mishmar, Dan, Ben-Zvi, Anat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829988/
https://www.ncbi.nlm.nih.gov/pubmed/35139855
http://dx.doi.org/10.1186/s12915-022-01241-2
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author Meshnik, Lana
Bar-Yaacov, Dan
Kasztan, Dana
Neiger, Tali
Cohen, Tal
Kishner, Mor
Valenci, Itay
Dadon, Sara
Klein, Christopher J.
Vance, Jeffery M.
Nevo, Yoram
Züchner, Stephan
Ovadia, Ofer
Mishmar, Dan
Ben-Zvi, Anat
author_facet Meshnik, Lana
Bar-Yaacov, Dan
Kasztan, Dana
Neiger, Tali
Cohen, Tal
Kishner, Mor
Valenci, Itay
Dadon, Sara
Klein, Christopher J.
Vance, Jeffery M.
Nevo, Yoram
Züchner, Stephan
Ovadia, Ofer
Mishmar, Dan
Ben-Zvi, Anat
author_sort Meshnik, Lana
collection PubMed
description BACKGROUND: Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, such as replicative segregation, mitochondrial bottlenecks, and selection, may modulate the exitance of heteroplasmic mutations. Since such mutations may have pathological consequences, they likely survive and are inherited due to functional complementation via the intracellular mitochondrial network. Here, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. RESULTS: We assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin (fzo-1). Animals displayed severe embryonic lethality and developmental delay. Strikingly, observed phenotypes were relieved during subsequent generations in association with complete loss of ΔmtDNA molecules. Moreover, deletion loss rates were negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. Introducing the ΔmtDNA into a fzo-1;pdr-1;+/ΔmtDNA (PARKIN ortholog) double mutant resulted in a skewed Mendelian progeny distribution, in contrast to the normal distribution in the fzo-1;+/ΔmtDNA mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. CONCLUSIONS: Taken together, our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection while inherited through generations. Moreover, our findings underline the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-022-01241-2.
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spelling pubmed-88299882022-02-10 Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness Meshnik, Lana Bar-Yaacov, Dan Kasztan, Dana Neiger, Tali Cohen, Tal Kishner, Mor Valenci, Itay Dadon, Sara Klein, Christopher J. Vance, Jeffery M. Nevo, Yoram Züchner, Stephan Ovadia, Ofer Mishmar, Dan Ben-Zvi, Anat BMC Biol Research Article BACKGROUND: Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, such as replicative segregation, mitochondrial bottlenecks, and selection, may modulate the exitance of heteroplasmic mutations. Since such mutations may have pathological consequences, they likely survive and are inherited due to functional complementation via the intracellular mitochondrial network. Here, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance. RESULTS: We assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin (fzo-1). Animals displayed severe embryonic lethality and developmental delay. Strikingly, observed phenotypes were relieved during subsequent generations in association with complete loss of ΔmtDNA molecules. Moreover, deletion loss rates were negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. Introducing the ΔmtDNA into a fzo-1;pdr-1;+/ΔmtDNA (PARKIN ortholog) double mutant resulted in a skewed Mendelian progeny distribution, in contrast to the normal distribution in the fzo-1;+/ΔmtDNA mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes. CONCLUSIONS: Taken together, our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection while inherited through generations. Moreover, our findings underline the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12915-022-01241-2. BioMed Central 2022-02-09 /pmc/articles/PMC8829988/ /pubmed/35139855 http://dx.doi.org/10.1186/s12915-022-01241-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research Article
Meshnik, Lana
Bar-Yaacov, Dan
Kasztan, Dana
Neiger, Tali
Cohen, Tal
Kishner, Mor
Valenci, Itay
Dadon, Sara
Klein, Christopher J.
Vance, Jeffery M.
Nevo, Yoram
Züchner, Stephan
Ovadia, Ofer
Mishmar, Dan
Ben-Zvi, Anat
Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
title Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
title_full Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
title_fullStr Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
title_full_unstemmed Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
title_short Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
title_sort mutant c. elegans mitofusin leads to selective removal of mtdna heteroplasmic deletions across generations to maintain fitness
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8829988/
https://www.ncbi.nlm.nih.gov/pubmed/35139855
http://dx.doi.org/10.1186/s12915-022-01241-2
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